It has been difficult to administer protein/peptide substances orally because of their low bioavailabilities (BA) due to the extensive degradation both in the stomach and in the small intestine by digestive enzymes and hydrochloric acid. On the other hand, large intestine has been drawn less attention as absorption sites for drugs because large intestine was considered not to contain transport system for nutrient. Recently, it has been demonstrated that physiologically active polypeptide hormones are absorbed at large intestine, and so, large intestine have drawn attention as an absorption site for protein/peptide drugs. The following conventional drug delivery techniques have been used to deliver drugs to the lower intestines including lower part of small intestine, large intestine, colon and etc.; 1) colon specific polymer-coated preparations that are soluble in large intestines (for example, Science vol. 233: 1081-1084, 1986 and KAGAKU KOGYO 1991, october, p 55-63), and 2) drug release-controlling systems, taking advantages of osmotic pressure, so called "TES" (Time-controlled Explosion System that contains drug layer, swellable layer and water-insoluble polymer membranes) preparations (see, for example, Japanese patent publication KOKAI No. 62-30709 and Pharm. Tech. Japan vol. 7: 711-718, 1991), and 3) time-controlled drug release capsule such as Pulsincap.RTM. system using a swellable polymer stopper (see, for example, W090/09168, 1990) and so forth have been known.
Also, drugs for the treatment of the inflammatory bowel disease (IBD) such as 5-aminosalicylic acid (5ASA) is used as a pro-drug, sulfasalazine that is an azo compound of 5ASA with sulfapyridine, because of extensive absorption of 5ASA during passage through the small intestine. As the target site of 5ASA is large intestine, to which an extremely small amount of 5ASA orally administered is delivered. Therefore, instead of 5ASA, its pro-drug sulfasalazine has been used clinically. However, side effects due to the hydrolyzed product, sulfapyridine, are now in great clinical problem.
Furthermore, it has also been difficult to administer anti-cancer drugs orally, because of the necrosis of the GI tract due to the exposure to high concentration of the anti-cancer drug molecules dissolved in the GI tract. Conventional oral slow-release tablets can control the release profile of anti-cancer drugs. However, these tablets contact directly to the mucosal surface of the GI tract. Therefore, the possibility of necrosis is high.
Since colon specific polymers and a polymer used in Pulsincap are new polymer, only insufficient data regarding their safeties are available. Additionally, time-controlled release system like TES, using osmotic pressure, a large amount of drug are required per batch because drug is coated onto the Nonpareils.RTM. (granule of sucrose; Freund Co., Ltd.) seeds with a spraying binder (e.g. hydroxypropyl-methylcellulose etc.) in centrifugal granulator or blown up by air in fluid bed granulator. Therefore, these systems may not be practical if the drugs are expensive. In addition, in the case of pro-drug, especially new pro-drug compounds, data concerning their safeties are necessary for developing as therapeutic drugs.
As the result of an extensive study to overcome the above drawbacks and problems in conventional slow-release tablets, it has now been discovered preparations of the present invention which prevents the direct contact of drug molecules in the preparations to mucosal surface of the GI tract.